Sleep is the Price the Brain Pays for Learning

Why do animals ranging from fruit flies to humans all need to sleep? After all, sleep disconnects them from their environment, puts them at risk and keeps them from seeking food or mates for large parts of the day.

Two leading sleep scientists from the University of Wisconsin School of Medicine and Public Health say that their synaptic homeostasis hypothesis of sleep or “SHY” challenges the theory that sleep strengthens brain connections.

The SHY hypothesis, which takes into account years of evidence from human and animal studies, says that sleep is important because it weakens the connections among brain cells to save energy, avoid cellular stress, and maintain the ability of neurons to respond selectively to stimuli.

“Sleep is the price the brain must pay for learning and memory,” says Dr. Giulio Tononi, of the UW Center for Sleep and Consciousness. “During wake, learning strengthens the synaptic connections throughout the brain, increasing the need for energy and saturating the brain with new information. Sleep allows the brain to reset, helping integrate newly learned material with consolidated memories, so the brain can begin anew the next day.”

Tononi and his co-author Dr. Chiara Cirelli, both professors of psychiatry, explain their hypothesis in a review article in today’s issue of the journal Neuron. Their laboratory studies sleep and consciousness in animals ranging from fruit flies to humans; SHY takes into account evidence from molecular, electrophysiological and behavioral studies, as well as from computer simulations.”Synaptic homeostasis” refers to the brain’s ability to maintain a balance in the strength of connections within its nerve cells.

Why would the brain need to reset? Suppose someone spent the waking hours learning a new skill, such as riding a bike. The circuits involved in learning would be greatly strengthened, but the next day the brain will need to pay attention to learning a new task. Thus, those bike- riding circuits would need to be damped down so they don’t interfere with the new day’s learning.

“Sleep helps the brain renormalize synaptic strength based on a comprehensive sampling of its overall knowledge of the environment,” Tononi says, “rather than being biased by the particular inputs of a particular waking day.” 

The reason we don’t also forget how to ride a bike after a night’s sleep is because those active circuits are damped down less than those that weren’t actively involved in learning. Indeed, there is evidence that sleep enhances important features of memory, including acquisition, consolidation, gist extraction, integration and “smart forgetting,” which allows the brain to rid itself of the inevitable accumulation of unimportant details.

However, one common belief is that sleep helps memory by further strengthening the neural circuits during learning while awake. But Tononi and Cirelli believe that consolidation and integration of memories, as well as the restoration of the ability to learn, all come from the ability of sleep to decrease synaptic strength and enhance signal-to-noise ratios.

While the review finds testable evidence for the SHY hypothesis, it also points to open issues. One question is whether the brain could achieve synaptic homeostasis during wake, by having only some circuits engaged, and the rest off-line and thus resetting themselves.

Other areas for future research include the specific function of REM sleep (when most dreaming occurs) and the possibly crucial role of sleep during development, a time of intense learning and massive remodeling of brain.

Want a good night’s sleep in the new year? Quit smoking

As if cancer, heart disease and other diseases were not enough motivation to make quitting smoking your New Year’s resolution, here’s another wake-up call: New research published in the January 2014 issue of The FASEB Journal suggests that smoking disrupts the circadian clock function in both the lungs and the brain. Translation: Smoking ruins productive sleep, leading to cognitive dysfunction, mood disorders, depression and anxiety.

"This study has found a common pathway whereby cigarette smoke impacts both pulmonary and neurophysiological function. Further, the results suggest the possible therapeutic value of targeting this pathway with compounds that could improve both lung and brain functions in smokers," said Irfan Rahman, Ph.D., a researcher involved in the work from the Department of Environmental Medicine at the University of Rochester Medical Center in Rochester, N.Y. "We envisage that our findings will be the basis for future developments in the treatment of those patients who are suffering with tobacco smoke-mediated injuries and diseases.

Rahman and colleagues found that tobacco smoke affects clock gene expression rhythms in the lung by producing parallel inflammation and depressed levels of brain locomotor activity. Short- and long- term smoking decreased a molecule known as SIRTUIN1 (SIRT1, an anti-aging molecule) and this reduction altered the level of the clock protein (BMAL1) in both lung and brain tissues in mice. A similar reduction was seen in lung tissue from human smokers and patients with chronic obstructive pulmonary disease (COPD). They made this discovery using two groups of mice which were placed in smoking chambers for short-term and long-term tobacco inhalation. One of the groups was exposed to clean air only and the other was exposed to different numbers of cigarettes during the day. Researchers monitored their daily activity patterns and found that these mice were considerably less active following smoke exposure.

Scientists then used mice deficient in SIRT1 and found that tobacco smoke caused a dramatic decline in activity but this effect was attenuated in mice that over expressed this protein or were treated with a small pharmacological activator of the anti-aging protein. Further results suggest that the clock protein, BMAL1, was regulated by SIRT1, and the decrease in SIRT1 damaged BMAL1, resulting in a disturbance in the sleep cycle/molecular clock in mice and human smokers. However, this defect was restored by a small molecule activator of SIRT1.

"If you only stick to one New Year’s resolution this year, make it quitting smoking," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “Only Santa Claus has a list longer than that of the ailments caused or worsened by smoking. If you like having a good night’s sleep, then that’s just another reason to never smoke.”

Disease and sleep: Recent studies find new links

One in five U.S. adults shows signs of chronic sleep deprivation, and a shortage of sleep has been linked to health problems as different as diabetes and Alzheimer’s disease. Recent studies have found some interesting connections between illness and what is happening in our brains as we snooze.

Sleep to protect your brain

A new study from Uppsala University, Sweden, shows that one night of sleep deprivation increases morning blood concentrations of NSE and S-100B in healthy young men. These molecules are typically found in the brain. Thus, their rise in blood after sleep loss may indicate that a lack of snoozing might be conducive to a loss of brain tissue. The findings are published in the journal SLEEP.

Fifteen normal-weight men participated in the study. In one condition they were sleep-deprived for one night, while in the other condition they slept for approximately 8 hours.

“We observed that a night of total sleep loss was followed by increased blood concentrations of NSE and S-100B. These brain molecules typically rise in blood under conditions of brain damage. Thus, our results indicate that a lack of sleep may promote neurodegenerative processes”, says sleep researcher Christian Benedict at the Department of Neuroscience, Uppsala University, who lead the study. 

“In conclusion, the findings of our trial indicate that a good night’s sleep may be critical for maintaining brain health”, says Christian Benedict.

Crossing the channel: Surprising new findings in the neurology of sleep and vigilance

A recent neurological addressing one of the most fundamental issues in sleep rhythm generation study underscores an inconvenient truth—namely, that established scientific facts have and will continue to change. Researchers at Institute for Basic Science (Daejeon), Korea Institute of Science and Technology (Seoul) and Yonsei University (Seoul) have demonstrated significant exceptions to the theory, long accepted as dogma, that low-threshold burst firing mediated by T-type Ca²⁺channels in thalamocortical neurons is the key component for sleep spindles. (A T-type Ca²⁺channel is a type of voltage-gated ion channel that displays selective permeability to calcium ions with a transient length of activation. Burst firing refers to periods of rapid neural spiking followed by quiescent, silent, periods. Sleep spindles are bursts of oscillatory brain activity visible on an EEG that occurs during non-rapid eye movement stage 2, or NREM-2, sleep, during which no eye movement occurs, and dreaming is very rare.) The scientists presented both in vivo and in vitro evidence that sleep spindles are generated normally in the absence of T-type channels and burst firing (periods of rapid neural spiking followed by quiescent, silent, periods) in thalamocortical neurons. Moreover, their results show what they describe as a potentially important role of tonic (constant) firing in this rhythm generation. They conclude that future studies should be aimed at investigating the detailed mechanism through which each type of thalamocortical oscillation is generated.

Dr. Hee-Sup Shin and Prof. Eunji Cheong discussed the paper that they recently published in Proceedings of the National Academy of Sciences. “The previous theory implicated thalamocortical TC burst firing in all sleep waves which appear in different sleep stages,” Cheong tells Medical Xpress. “However, we’ve long questioned the extent to which thalamocortical T-type Ca²⁺ channels and the resulting burst firing contribute to the heterogeneity of thalamocortical oscillations during non-rapid eye movement sleep consisting of multiple brain waves.” A T-type Ca²⁺channel is a type of voltage-gated ion channel which displays selective permeability to calcium ions, in this case with a transient length of activation.

Shin notes that the scientists faced a number of issues in designing and interpreting the results of the in vivo and in vitro experiments to test their hypothesis. “Since we observed the quite intact sleep spindles in Ca_V3.1 knockout mice, we tried to figure out how the sleep spindles are generated in the absence of a thalamocortical burst.” (A gene knockout, or KO, is a genetic technique in which one of an organism’s genes is made inoperative to learn about its function from the difference between the knockout organism and normal individuals. Ca_V3.1 is a T-type calcium channel found in neurons, cells that have pacemaker activity.) “The issues were if the spindles are generated within the thalamocortical circuit as previously known, and how thalamocortical neurons generate spikes during spindles in the presence or absence of a thalamocortical burst.” All of the researchers’ the experiments were designed to investigate these questions.

"The purpose of in vitro thalamocortical-thalamic reticular nucleus,” or TC-TRN, “network oscillations was to show if thalamocortical oscillations observed in Ca_V3.1 knockout mice could be generated either within an intrathalamic network or if they were cortical driven oscillations,” Cheong points out. “Another difference between in vivo and in vitro networks is that compared to in vivo network all the afferent inputs into TC or TRN are not intact in an in vitro TC-TRN network.” The results showed that spindle-like oscillations were generated even in the absence of cortex.

The study shows that these differences also relate to In vivo data suggesting that TRN neurons are spindle pacemakers. “There have been debates on the leading role of TRN versus cortex in pacing the sleep spindles. In an in vitro TC-TRN network, both the afferent inputs and corticothalamic inputs onto TC neurons are not intact,” Shin explains. “Therefore, major inputs onto TC neurons in those experiments come from TRN neurons. The generation of intrathalamic oscillations under this condition indicates that the reciprocal connection between TRN and TC could generate the oscillations, which adds weight to the TRN neurons as spindle pacemakers. The generation of Ca_V3.1 knockout mice which lack T-type Ca²⁺ channels in TC neurons was the key to address this issue.”

Cheong emphasizes that the study’s major findings call into question the essential role of low-threshold burst firings in thalamocortical neurons. “It’s noteworthy that tonic spikes were more abundant than burst spikes during spindles even in wild Type thalamocortical neurons – not only in Ca_V3.1^-/- TC neurons – whereas no difference in tonic and burst spike frequency was seen during non-spindle periods. Moreover,” he continues, “the tonic spike frequency increases significantly during cortical spindle events compared to non-spindle periods even in wild-type TC neurons. This is clearly different from that seen for burst spike frequency in wild-type TC neurons, which occurred with almost equal incidence during both the spindle and non-spindle periods.” Therefore, Cheong points out, the scientists concluded that TC burst firing is not required for the generation in spindle generation.

The researchers also found that the peak frequency of sleep spindles was not different between wild and Ca_V3.1 KO mice, which suggested that TC spikes are not critical in determining the spindle frequency. However, Shin notes, the question of what drives TC neurons to fire during spindles remains to be further investigated, although they think that TC firing during spindles indicates that the TC-TRN network is not as simple as previously believed.

Moving forward, Cheong tells Medical Xpress, the researchers would like to further investigate the firing pattern of TC neurons during natural NREM sleep, including spindle, delta and slow waves. and also elucidate the detailed ensemble behavior of neuron within thalamocortical network during sleep. Moreover, TC burst firing has long been implicated in both physiological thalamocortical oscillations during both sleep and pathological thalamocortical oscillations, such as spike-wave-discharges appearing in absence epilepsy. “Our current study clearly showed that TC burst are not essential for sleep spindles, which would be helpful information to develop the anti-epileptic agents,” Shin concludes.

Enzyme that produces melatonin originated 500 million years ago

An international team of scientists led by National Institutes of Health researchers has traced the likely origin of the enzyme needed to manufacture the hormone melatonin to roughly 500 million years ago.

Their work indicates that this crucial enzyme, which plays an essential role in regulating the body’s internal clock, likely began its role in timekeeping when vertebrates (animals with spinal columns) diverged from their nonvertebrate ancestors.

An understanding of the enzyme’s function before and after the divergence may contribute to an understanding of such melatonin-related conditions as seasonal affective disorder, jet lag, and to the understanding of disorders involving vision.

The findings provide strong support for the theory that the time-keeping enzyme originated to remove toxic compounds from the eye and then gradually morphed into the master switch for controlling the body’s 24-hour cyclic changes in function.

The researchers isolated a second, nonvertebrate form of the enzyme from sharks and other contemporary animals thought to resemble the prototypical early vertebrates that lived 500 million years ago.

The study, published online in PNAS, was conducted by senior author David C. Klein, Ph.D., Chief of the Section on Neuroendocrinology in the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and colleagues at NIH, and at institutions in France, Norway, and Japan.

Melatonin is a key hormone that regulates the body’s day and night cycle. Dr. Klein explained that it is manufactured in the brain’s pineal gland and is found in small amounts in the retina of the eye. Melatonin is produced from the hormone serotonin, the end result of a multistep sequence of chemical reactions. The next-to-last step in the assembly process consists of attaching a small molecule — the acetyl group — to the nearly finished melatonin molecule. This step is performed by an enzyme called arylalkylamine N-acetyltransferase, or AANAT.

Because of its key role in producing the body clock-regulating melatonin, AANAT is often referred to as the timezyme, Dr. Klein added.

The form of AANAT found in vertebrates occurs in the brain’s pineal gland and, in small amounts, in the retina. Another form of the enzyme, termed nonvertebrate AANAT, has been found only in other forms of life, such as bacteria, plants and insects.

“Nonvertebrate AANAT appears to detoxify a broad range of potentially toxic chemicals,” Dr. Klein said. “In contrast, vertebrate AANAT is highly specialized for adding an acetyl group to melatonin. The two are as different from each another as a Ferrari is from a Model-T Ford, considering the speed of the reaction and how fast it can be turned on and off.”

In 2004, Dr. Klein and his coworkers published a theory that melatonin was at first a kind of cellular waste, a by-product created in cells of the eye when normally toxic substances were rendered harmless. Because melatonin accumulated at night, the ancestors of today’s vertebrates became dependent on melatonin as a signal of darkness. As the need for greater quantities of melatonin grew, the pineal gland developed as a structure separate from the eyes, to keep serotonin and other toxic substances needed to make melatonin away from sensitive eye tissue.

“The pineal glands of birds and reptiles can detect light,” Dr. Klein said. “And the retinas of human beings and other species also make melatonin. So it would appear that both tissues evolved from a common, ancestral, light-detecting tissue.”

Before the current study, the researchers lacked proof of their theory, particularly in regard to the question of how the vertebrate form of the enzyme originated because it did not appear to exist in non-vertebrates and had been found only in bony fishes, reptiles, birds, and mammals — all of which lacked the non-vertebrate form.

The first evidence of how the vertebrate form of the enzyme originated came when study co-author Steven L. Coon, also of NICHD, discovered genes for the nonvertebrate and vertebrate forms of AANAT in genomic sequences from the elephant shark, considered to be a living representative of early vertebrates.

This finding indicated that the vertebrate form of AANAT may have resulted after a phenomenon known as gene duplication, Dr. Klein said. Gene duplication, he added, typically results from any of a number of genetic mishaps during cell division. Instead of one copy of a gene resulting from the process, an additional copy results, so that there are two versions of a gene where only one existed previously. The phenomenon is thought to be a major factor influencing evolutionary change.

The researchers theorized that following duplication, one form of AANAT remained unchanged and the other gradually evolved into the vertebrate form. Dr. Klein said that at some point after vertebrate AANAT developed, vertebrates appear to have stopped making the nonvertebrate form, perhaps because it was no longer needed or because its function was replaced by a similar enzyme.

Before the researchers could continue, they needed to confirm their finding, to rule out that the nonvertebrate AANAT they found didn’t result from accidental contamination with bacteria or some other organism. The NICHD researchers sought assistance from other research teams around the world. DNA from Mediterranean sharks and sea lampreys was obtained via fishermen’s catches by Jack Falcon of the Arago Laboratory, a marine biology facility that is part of the CNRS and the Pierre and Marie Curie University in France. Samples from a close relative of the elephant shark — the ratfish — were provided by Even-Jorgensen at the Arctic University of Norway. Finally, Susumo Hyodo of the University of Tokyo contributed samples from elephant sharks he collected off the coast of Australia.

Next, the Hyodo and Falcon groups isolated RNA from the retinas and pineal glands of the animals. RNA is used to direct the assembly of amino acids into proteins. From these RNA sequences, it was possible to assemble working versions of AANAT molecules — both the vertebrate and nonvertebrate forms.

The sequences of the proteins encoded by the AANAT genes were analyzed by Eugene Koonin and Yuri Wolf of the National Library of Medicine using computer techniques designed to study evolution. Peter Steinbach, of NIH’s Center for Information Technology, examined the three-dimensional structures of nonvertebrate and vertebrate AANAT in the study animals and determined that the two forms of the enzyme likely had a common ancestor.

Taken together, their results provide evidence for the hypothesis that nonvertebrate AANAT resulted from duplication of the non-vertebrate AANAT gene about 500 million years ago and that following this event one copy of the duplicated gene eventually changed into the gene for vertebrate AANAT.

In addition to providing information on the origin of melatonin and the evolution of AANAT, the findings also have implications for research on disorders affecting vision. Vertebrate AANAT and melatonin are found in small amounts in the eyes of humans and other vertebrates. Although they may play a role in detoxifying compounds, it is also reasonable to consider that this detoxifying function is shared with other enzymes.

“It’s possible that a malfunction in these other enzymes might lead to an accumulation of chemicals known as arylalkamines — in the same family as serotonin — and this might contribute to eye disease,” Dr. Klein said. “Consequently, research into how these enzymes function might lead to therapies to protect vision.”

Five mysteries of the brain

For centuries, the brain was a mystery. Only in the last few decades have scientists begun to unravel its secrets. In recent years, using the latest technology and powerful computers further key discoveries have been made.

However, much remains to be understood about how the brain works. Here are five important areas of study attempting to unlock the last secrets of the brain.

How to fix it

When we think, move, speak, dream and even love - it all happens in the grey matter. But our brains are not simply one colour. White matter matters too.

Much of the research into dementia has focused on the tell-tale plaques of beta amyloid and tau protein tangles which occur in the grey matter.

But one British scientist, Dr Atticus Hainsworth says the white matter - and its blood supply - may be equally important.

The white colour results from fatty sheaths around the axons - which are extensions of the nerve cell bodies and help the cells to communicate.

He is using banks of donated brains, in Oxford and Sheffield, to analyse white matter for potential triggers such as leaking blood vessels.

"Some of the cases had an MRI or CT scan and that information can help give more clues about whether there was disease in the white matter - and what its basis might be," says Dr Hainsworth.

If leaking blood vessels in white matter do play a key role in the development of dementia then it may offer up a another potential route for new drug therapies.

How to make us all geniuses

For years caffeine was used to enhance alertness. But popping a pill to get straight-A’s may soon become the norm.

At Cambridge University neuroscientist Barbara Sahakian is investigating cognitive enhancers - drugs which make us smarter.

She studies how they can improve the performance of surgeons or pilots and asks if they could even be used to make us more entrepreneurial.

But she warns that there is no long-term safety information on these drugs and as a society we need to talk about their use.

She says the scientific and ethical challenges created by drugs which affect the production of brain chemicals like dopamine and noradrenaline - which induce pleasurable or “fight or flight” responses - need to be debated in order to decide whether drug-tests become routine before taking an exam.

Dr Sahakian adds: “I frequently talk to students about cognitive-enhancing drugs and a lot of students take them for studying and exams.

"But other students feel angry about this, they feel those students are cheating."

How can we harness our unconscious?

People need to be on top of their game when mastering skills like playing a musical instrument or detecting a bomb.

But research suggests that our unconscious can be harnessed to help us excel.

Repeatedly playing a tricky piece of music obviously helps develop a familiarity with the bits that are most difficult.

But cellist Tania Lisboa, who’s also a researcher in the Centre for Performance Science at London’s Royal College of Music, says it also helps to send the trickier parts of a piece from her conscious to the unconscious part of her brain.

After hours of practice, a fluent musician’s brain stores how to play the piece in an area at the back of the brain called the cerebellum - literally “the little brain”.

Neuroscientist Prof Anil Seth, of Sussex University, says: “It has more brain cells than the rest of the brain put together.

"It helps to promote fluid movements.. So the conscious effort of learning how to bow a cello is moved from the cortical areas which are involved when it’s new or difficult over to the cerebellum, which is very good at producing unconscious fluent behaviour on demand."

Music and defence may not appear to have much in common, but the unconscious can also help detect potential threats, whether it’s a suspicious person in a crowd or the presence of an improvised explosive device.

The unconscious brain is really good at spotting patterns - a skill which Paul Sajda at Colombia University in New York exploits - right at the boundary of the conscious/sub-conscious.

"I can flash 10 images a second and if one of those images has something out of the ordinary..that will essentially cause me to re-orient my brain to that image - but I’m not exactly aware of what that is."

Brain activity is monitored whilst the analyst looks at images so that researchers can later see which images triggered reactions.

What dreams are for

It’s just 60 years since scientists in Chicago first noted the tell-tale “rapid eye movement” or REM sleep which we now associate with dreaming.

But our fascination with dreams dates back at least 5,000 years to ancient Mesopotamia when people believed that the soul moved out of a sleeping body to visit the places they dreamed of.

REM sleep - which occurs every 90 minutes or so - begins with signals from the base of the brain which eventually reach the cerebral cortex - the outer layer of the brain which is responsible for learning and thought.

These nerve impulses are also directed to the spinal cord, inducing temporary paralysis of the limbs.

Prof Robert Stickgold, from the Beth Israel Deaconess Medical Center for Sleep and Cognition in Boston, believes that dreams are vital for processing memory associations.

He has asked the subjects of some of his sleep studies to play Tetris - and then noted their descriptions of how they floated amongst geometric shapes in their dreams.

He’s an admirer of Japanese scanning research where the scientists could “read” the dreams of subjects as they had MRI scans.

But he says it’s hard to get people to sleep in a noisy, expensive scanner.

And the future? “I would like to see research which reveals the rules for dream construction - and how it relates to the larger concept of memory processing during sleep.”

One even more elusive goal: how to dream just happy dreams and ditch the bad ones, especially nightmares.

Can we cure unreachable pain?

Excruciating chronic pain is one of medicine’s most difficult problems to solve.

Untouched by conventional treatments like painkilling drugs, surgeons are now testing their theory that deep brain stimulation could provide relief.

It is a brain surgery technique which involves electrodes being inserted to reach targets deep inside the brain.

The target areas are stimulated via the electrodes which are connected to a battery-powered pacemaker surgically placed under the patient’s collar bone.

One of the pioneers of this technique is Prof Tipu Aziz at the John Radcliffe Hospital in Oxford.

Deep brain stimulation has been used in the past for Parkinson’s disease and depression, and is now being trialled on obsessive compulsive disorder patients as well as those in chronic pain.

One of his patients, Clive, has suffered from terrible pain for nearly a decade after an operation to remove a disc in his neck.

"Sometimes I thought that if I had an axe, I’d chop my own arm off, if I thought it would get rid of the pain."

The doctors explained to him that his brain was getting signals from his arm to his brain confused and that the electrodes could help.

In Clive’s case this was an area of the brain called the anterior cingulate.

A week after his surgery he was one of the fortunate 70% of patients for whom the deep brain stimulation provides relief.

"It’s great to be out of that pain now. Since having the implant I can sit down for longer, I am able to walk further, everything is an improvement."

Prof Aziz is treating medical conditions. But he is aware of ethical dilemmas which could arise if the technique was applied to other areas.

"Putting electrodes in targets to improve memory.

"Or you could put electrodes into people to make them indifferent to danger and create the perfect soldier."